The incidence of type 2 Diabetes Mellitus (t2DM) is increasing at an alarming rate both nationally and worldwide with more than 1 million new cases per year diagnosed in the US alone. Although weight- loss has been shown to be successful in delaying diabetes, it is difficult to achieve and maintain long- term. Therefore, identification of weight-independent environmental and easily modified risk factors is urgently needed to prevent the increase in the incidence of t2DM. Vitamin D and calcium are two nutritional factors that have been suspected as modifiers of diabetes risk based on animal and human studies including our own observational data. However, there are critical gaps in our knowledge about the magnitude of the clinical effect of vitamin D and calcium on diabetes risk, including uncertainty about their potential physiologic mechanism of action in relation to t2DM. Currently, this lack of data limits the usefulness of vitamin D and calcium as feasible nutritional interventions for prevention of t2DM. The central hypothesis of the proposed study is that, vitamin D and calcium insufficiency are risk factors for the development of t2DM and that the risk is mediated by changes in pancreatic beta- cell function, insulin sensitivity, and systemic inflammation. We plan to test our main hypothesis by pursuing a dual approach (observational study and experimental human trial) to achieve the following 2 specific aims. (1). Assess the magnitude of the association between vitamin D status and risk of t2DM in a nested case-control study design in women in a large prospective cohort, the Nurses' Health Study. The working hypothesis is that vitamin D status, as measured by serum 25OHD level, is inversely associated with t2DM risk. The association will be quantified (2). Determine the effects of vitamin D and Calcium supplementation on beta-cell function, insulin sensitivity, glucose tolerance and systemic inflammation in a 3-month randomized placebo-controlled trial of adults at risk for t2DM given vitamin D3 and calcium carbonate (2x2 factorial design). The working hypothesis is that vitamin D and calcium supplementation improves beta-cell function and insulin sensitivity (primary outcomes) and systemic inflammation and glucose tolerance (secondary outcomes). Our results will provide novel and important data that will serve as the foundation for the rational integration of these nutrients into conventional medical care to ameliorate t2DM burden. [unreadable] [unreadable] [unreadable]